P865: BIOMARKER ANALYSIS TO SUPPORT DOSE OPTIMIZATION OF IBERDOMIDE AS MONOTHERAPY AND IN COMBINATION WITH STANDARD OF CARE TREATMENTS FOR MULTIPLE MYELOMA FROM A PHASE 1/2 TRIAL
Authors: M. Amatangelo, Y. Cheng, W. Pierceall, N. W. van de Donk, S. Lonial, M. Wang, J. Emerson, K. Hong, P. Maciag, T. Peluso, A. Gandhi, A. Thakurta
Journal: HemaSphere (2022)

Background: Iberdomide (IBER), a novel cereblon E3 ligase modulator (CELMoD®) compound, induces ubiquitination and proteasome-dependent degradation of Ikaros and Aiolos proteins, resulting in tumoricidal and immunomodulatory activity in multiple myeloma (MM). IBER is being investigated for the treatment of relapsed/refractory MM (RRMM) in a phase 1/2 study (NCT02773030). Due to the recent focus by health authorities on dose selection for oncology products other than the maximum tolerated dose (MTD), a comprehensive analysis of pharmacodynamics (PD) and pharmacokinetics (PK) was implemented to support dose optimization of IBER. Aims: To inform dose selection of IBER as monotherapy, and in combination with dexamethasone (DEX; Iber+d) and with DEX and daratumumab (DARA; IberDd). Methods: PK samples were collected on treatment of cycles (C) 1–4 to estimate IBER exposure using population PK (area under the concentration curve over 24-h dosing interval [AUCτ]). Biomarkers included analysis of peripheral blood samples on C1 day (D)1 and mid-cycle through C4 for immunophenotyping, absolute neutrophil counts (ANC), and assessment of serum free light chain (sFLC), as a biomarker of tumor burden. Bone marrow samples were collected at screening and C2D15 for immunohistochemistry. Results: IBER AUCτ increased in a dose-proportional manner between 0.3 and 1.0 mg as monotherapy and 0.3 and 1.6 mg in combination with DEX, with moderate variability. Median time to maximum serum concentration of IBER was 2–4 h post dose with an elimination half-life of ~12 h. Comparable IBER exposure was observed between monotherapy and Iber+d. Reductions in Ikaros/Aiolos protein levels in tumor cells were observed at all dose levels in both cohorts with a >90% reduction at the 0.45-mg dose. However, a >50% decrease in sFLCs was observed only at doses ≥0.9 mg, and doses of 1.6 mg induced faster and deeper decreases vs lower doses. In the immune compartment, IBER treatment induced similar dose-/exposure-dependent PD changes as monotherapy and Iber+d, which appeared to saturate at higher doses. A >80% reduction in mature B cells and ~2-fold increase in proliferating/activated T and NK cells were observed at doses ≥1.0 mg. PD activity of IBER was not attenuated by prior refractoriness to immunomodulatory drugs (IMiD® agents) or anti-CD38 therapy. Based on these results, doses between 1.0 and 1.6 mg were tested in the IberDd cohort. PK and PD of IBER were similar with concomitant administration of DARA. In this cohort, a reduction in mature B cells and sFLCs was more consistently observed at 1.6 mg vs lower doses; however, higher IBER exposures were associated with more pronounced decreases in ANC when compared with Iber+d. This was clinically manageable and the MTD of IBER was not determined in any cohort. Summary/Conclusion: Similar PK and PD results were observed in patients treated with IBER monotherapy, Iber+d, and IberDd. Across all cohorts, a >20% difference in dose was needed for meaningful change in IBER exposure, immune PD began to saturate at doses ≥1.0 mg, and decreases in tumor burden were greatest at the 1.6-mg dose. Based on these results, IBER doses of 1.0, 1.3, and 1.6 mg were chosen for dose optimization of IberDd for RRMM. Taken together with data suggesting immune surveillance is a driver of maintenance therapy efficacy and a desire to increase IBER tolerability with long-term treatment, doses of 0.75, 1.0, and 1.3 mg were selected for dose optimization of IBER monotherapy in the newly diagnosed MM maintenance setting.